Chromone derivatives

ABSTRACT

The present invention relates to novel chromone derivatives, which are shown by the following general formula ##STR1## wherein n is 0 or 1, m is 0, 1 or 2 when each of R&#39;s represents halogen, nitro, straight or branched alkyl having 1 to 6 carbon atoms, cyclic alkyl having 3 to 6 carbon atoms or butadienylene (--CH═CH--CH═CH--) which forms a benzene ring with any two adjacent carbon atoms at positions 5, 6, 7 and 8, --COOR&#39;, wherein R&#39; is hydrogen, lower alkyl, aralkyl, carboxamide which may be unsubstituted or substituted by at least one lower alkyl or aralkyl, or amino group which may be unsubstituted or substituted by R&#39;CO--, wherein R&#39; is a straight or branched chain alkyl or aryl, or lower alkyl, aralkyl or aryl, m is 0 or 1 when each of R&#39;s represents hydroxy, lower alkoxy or R&#39;COO--, wherein R&#39; is a straight or branched chain alkyl or aryl. The novel derivatives are useful as intermediates for chromones having effective anti-allergic action.

This is a divisional of Ser. No. 349,848, filed Apr. 10, 1973, now U.S.Pat. No. 3,896,114.

The present invention relates also to a process for the production ofthese chromone derivatives.

Hitherto, there have been known many kinds of anti-histamine agents, andsome of them have been put into practical use. However, aforesaid knownanti-histamine agents are not very satisfactory in view of one or moreof such drawbacks as showing rather low anti-allergic activity andrather high toxicity and causing side effects (e.g. sedation, cardiacstimulation and headache) upon long-term administration.

Moreover, most of the known anti-histamine agents show only antagonismtowards histamine released or produced in a living body and, thus, theyare not satisfactory as a medicine for treating allergic disease whichis caused by other allergy mediating substances, e.g. SRSA (SlowReacting Substance of Anaphylaxis) than histamine.

The inhibition of the secretion of chemical mediators, such as SRSA andhistamine, is very effective for the treatment of allergic disease, e.g.bronchial asthma. Hithertofore, however, no one has succeeded insynthesizing any compound in compliance with this purpose, at least froma practical or an industrial point of view.

Under these circumstances, present inventors have made extensive studiesand succeeded in synthesizing specific new chromone derivatives (I)defined below, which have never previously been synthesized. ##STR2##

Moreover, the present inventors have also unexpectedly found that thesecompounds have a very strong action in preventing the secretion of SRSAand histamine from the cells of a living body, and they also show quitea low toxicity; furthermore, they show the above actions effectivelyeven upon oral administration.

In view of these characteristics, the chromone derivatives of formula Ican be used as an effective medicine for preventing and/or treatingallergic diseases, especially bronchial asthma and rhinitis, by means oforal administration.

In the general formula (I), the alkyl group represented by the symbol Rmay be any of straight, branched or cyclic ones having 1 to 6 carbonatoms. Typical examples of the alkyl group may be methyl, ethyl, propyl,isopropyl, butyl, iso-butyl, sec.-butyl, tert.-butyl, pentyl,cyclopentyl, hexyl and cyclohexyl. Among them, for practical purposes,lower alkyl groups having 1 to 3 carbon atoms are preferred. The loweralkoxy group represented by the symbol R may be preferably that having 1to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxyand isobutoxy. The acyloxy group represented by the symbol R may belower alkyl carbonyloxy group whose alkyl moiety is that having 1 to 3carbon atoms, and aryl carbonyloxy group. Typical examples of theacyloxy group may be acetoxy, propionyloxy, butyryloxy and benzoyloxy.The carboxy group R which may be esterified is represented by theformula --COOR', wherein R' represents hydrogen atom, lower alkyl grouphaving 1 to 3 carbon atoms or aralkyl group. The lower alkyl grouprepresented by the symbol R' is that having 1 to 3 carbon atoms, such asmethyl, ethyl, propyl and isopropyl, and typical examples of the aralkylgroup represented by the symbol R' may be benzyl, phenethyl. The alkylsubstituted carboxamide group represented by the symbol R includes mono-or dialkyl substituted ones whose alkyl moiety is lower alkyl one having1 to 3 carbon atoms and mono- or diaralkyl (e.g. benzyl) substitutedones. Typical examples of these groups may be N-methyl-carboxamide,N,N-dimethyl carboxamide, N-ethyl carboxamide, N,N-diethylcarboxamide,N-propyl carboxamide, N-benzyl carboxamide and N,N-dibenzyl carboxamide.The acyl-substituted amino group represented by the symbol R includes anamino group substituted by lower alkylcarbonyl group whose alkyl moietyis that having 1 to 3 carbon atoms and an amino group substituted byarylcarbonyl group. Typical examples of these group may be acetylamino,propionylamino, butyrylamino and benzoylamino. Thehydrocarbon-substituted amino group represented by the symbol R includesmono- or di-lower alkyl substituted ones whose alkyl moiety is thathaving 1 to 3 carbon atoms, mono- or diaryl (e.g. phenyl, naphthyl)substituted ones and mono- or diaralkyl (e.g. benzyl, phenethyl)substituted ones. Typical examples of these groups may be methylamino,ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino,dipropylamino, phenylamino, diphenylamino, benzylamino orphenethylamino. The halogen atom represented by the symbol R may bechlorine, bromine, iodine and fluorine.

In the present invention, the compounds of the general formula (I) areproduced by reacting the compound (II) ##STR3## wherein R, m and n havethe same meaning as defined above, with hydrazoic acid or a saltthereof.

The salt of hydrazoic acid employable in the present invention includessalts of hydrazoic acid with alkali metals or alkaline earth metals suchas lithium azide, sodium azide, potassium azide, magnesium azide,calcium azide, barium azide and strontium azide; the salts of hydrazoicacid with other metals capable of forming salts with hydrazoic acid,such as, aluminum azide, tin azide, zinc azide and titanium azide; andthe salts of hydrazoic acid with ammonia or organic amines (e.g.aniline, quinoline, imidazole).

In the reaction of the present invention, the salts of hydrazoic acidwith alkali metals also can be employed in combination with, forexample, a Lewis acid such as aluminum chloride, stannic chloride, zincchloride or titanium tetrachloride or ammonium chloride.

The amount of hydrazoic acid, a salt thereof or the Lewis acid or itsequivalent used in combination with the salt of hydrazoic acid isgenerally about 1 to 7 moles per mole of the starting compound (II) forpractical purposes.

Generally, the reaction is desirably carried out in an organic solvent.The solvent is exemplified by hydrocarbons such as benzene, toluene,petroleum ether; ethers such as tetrahydrofuran, dioxane, ethyl etherand ethylene glycol dimethyl ether; dimethylformamide; formamide;dimethylsulfoxide. While the reaction conditions including temperatureand time factors are largely optional, it is generally convenient tocarry out the reaction at room temperature to about 150° C. for about 1hour to about 2 days.

When a salt of hydrazoic acid is used as one of the starting compounds,the reaction of this invention yields the compound of the generalformula (I) in the form of the salt corresponding to the hydrazoate useddue to the acid function of the tetrazole ring. This salt, however, canbe easily converted to the object compound (I) possessing a freetetrazole ring by treating it with a suitable acid (e.g. a mineral acidsuch as hydrochloric acid or sulfuric acid).

The compound of the general formula (I) which can be obtained in theforegoing manner can be isolated and purified by procedures which areconventional per se (e.g. extraction, chromatography, recrystallization,etc.).

When the compound of the general formula (I) is substituted by alkoxy oracyloxy group(s), these alkoxy and acyloxy groups can be converted tohydroxyl groups by procedures of conventional dealkylation ordeacylation (e.g. hydrolysis with a hydrohalogenic acid such ashydrochloric acid, hydrobromic acid or hydroiodic acid and with amineral acid such as sulfuric acid).

Moreover, when the compound of the general formula (I) is substituted byacylamino group(s), the acylamino group can be converted to aminogroup(s) under conditions similar to the above conditions of hydrolysiswhich are conventionally used for the cleavage of amide bonds. On thecontrary, when the object compound of the general formula (I) issubstituted by hydroxy, amino or carboxy group(s), these groups can beconverted to acyloxy, acylamino, esterified carboxy or carboxamide groupwhich may be substituted by conventional acylation, esterification oramidation. Further, when the object compound of the general formula (I)has a free tetrazole ring, it can be converted to an organic amine salt,alkali metal salt or ammonium salt by reacting the compound of thegeneral formula (I) with an organic amine, e.g. ethanolamine,dl-methylephedrine, 1-(3,5-dihydroxyphenyl)-L-isopropylaminoethanol,isoproterenol, dextromethorphan, Hetrazan (diethylcarbamazine),diethylamine or triethylamine; an alkali metal hydroxide, e.g. sodiumhydroxide or potassium hydroxide; alkali metal carbonate, e.g. sodiumcarbonate or potassium carbonate; or ammonia in a per se conventionalmanner, e.g. by admixing and heating the reactants together in thepresence of an appropriate solvent (e.g. water, alcohol, dioxane,tetrahydrofuran).

The thus produced object compound (I) or their pharmaceuticallyacceptable salts, above all, the salts with the organic amines mentionedabove specifically, have an effective anti-allergic action and areuseful as medicines for allergic diseases such as allergic bronchialasthma, allergic dermatitis, allergic rhinitis and hay fever.

Further, since the alkali metal salts and organic amine salts of thecompound (I) are highly soluble in water, and the solutions so formedare stable, they lend themselves well to manufacturing suchpharmaceutical preparations as injections and solutions.

When the compounds of the general formula (I) or pharmaceuticallyacceptable salt thereof are employed as anti-allergic agents fortreating or preventing the above-mentioned allergic diseases, thesecompounds are administered per se or in the form of a pharmaceuticallyacceptable composition in admixture with suitable and conventionalcarriers or adjuvants.

The pharmaceutical composition may take the form of tablets, capsules,granules, powders, solution, injections, ointments, sprays or aerosolinhalants, and can be administered orally or parenterally. Especially,the compounds of the present invention show effective action even uponoral administration, and therefore they are very advantageous from apractical point of view.

The usual daily doses of the present compounds lie in the range of about1 to about 500 mg. more precisely of about 50 to 500 mg. upon oraladministration and about 1 to about 200 mg. upon parenteraladministration per adult human.

One of the starting compounds (II) of the present invention may beproduced by, for example, the following procedure: ##STR4## wherein Rand m have the same meaning as defined above.

The reaction of the Step (A) is conducted by reacting a compound of thegeneral formula (IV) with Vilsmeier reagent, which consists ofequivalent mole(s) of dimethylformamide and acid chloride such asphosphorus oxychloride, tetrachloropyrophosphate, thionylchloride,phosgene, phosphorus pentachloride, etc., in the presence or absence ofa suitable inert solvent. As the solvent, any solvent which does notrestrict the reaction may be employed. Typical examples of the solventare benzene, diethyl ether, petroleum benzine, chloroform or mixturesthereof.

The amount of the dimethylformamide and the acid chloride of Vilsmeierreagent is usually at least not less than 2 moles, preferably 10 to 12moles per mole of a compound of the general formula (IV), respectively.The reaction can proceed at room temperature under atmospheric pressure,but, if necessary, may be carried out under heating up to the boilingpoint of dimethylformamide or of the solvent used or cooling down to-30° C. or under heating and elevated pressure. The reaction time varieswith the reaction conditions such as temperature, pressure or kinds ofacid chloride and solvent used, but is generally from 25 minutes to 24hours.

The reaction of Step(B) is preferably conducted by reacting a compoundof the general formula (III) with hydroxylamine in the presence of asuitable solvent such as alcohols (e.g. methanol, ethanol and prepanol)or ether (e.g. dioxane and tetrahydrofuran).

While hydroxylamine may be the free base, it is preferable to employ thecorresponding hydrochloride. The amount of this reactant is usuallyabout 1 to about 4 moles per mole of the compound (III).

The reaction conditions including the reaction temperature and time arelargely optional, it is usually sufficient to conduct the reaction at 0°to 150° C. for 1 to 24 hours.

The reaction of Step(C) is conducted by reacting a compound of thegeneral formula (III) with cyanoacetic acid in a solvent and in thepresence of a base. The amount of cyanoacetic acid to be used in thisreaction is usually about 1 to 2 moles per mole of the compound of thegeneral formula (III).

The solvent is exemplified by hydrocarbons such as benzene, petroleumether, etc.; ethers such as methyl ether, ethyl ether, etc., andalcohols such as methanol, ethanol, etc. The base is exemplified bytertiary amines such as trimethylamine, triethylamine,N-methylpiperidine, N-methylmorpholine, N-methylpyrrolidine, etc;heteroaromatic compound such as pyridine, 2-methylpyridine,3methylpyridine, quinoline, 2-methylquinoline, imidazole,2-methylimidazole, etc. Among these compounds, heteroaromatic compoundsare the most desirable from all practical purposes. These bases may alsobe expected to function as the reaction solvent. The reaction conditionsincluding the reaction temperature and time cannot be stated in generalterms, for they depend upon the type of solvent and starting compoundsto be used. Generally speaking, it is desirable to conduct the reactionat room temperature to a temperature near the boiling point of thesolvent used, although one may conduct the reaction at a reducedtemperature, if required. The reaction time is usually about severalminutes to about 10 hours.

Incidentally, the above compound (IV) wherein R is amino group which maybe substituted by alkyl group may be produced by, for example, thefollowing procedures: ##STR5##

The above compound (IV) wherein R is amino group which is substituted byalkyl, aralkyl or acyl group may also be produced by reacting thecompound (C) with conventional alkylating, aralkylating or acylatingagent.

For example, the compound (IV) wherein R is dimethylamino group isproduced as follows;

Into a mixture of 10 weight parts of 2-hydroxy-5-nitro-acetophenone in200 volume parts of methanol and 22 volume parts of 37% aqueousformaldehyde solution is introduced at 25° C. 5500 volume parts ofhydrogen in the presence of 2 weight parts of palladium-carbon catalystand 5 volume parts of 2N-HCl. The resultant is filtered and concentratedto give 5-dimethylamino-2-hydroxyacetophenone as yellow needles meltingat 75°-76.5° C.

For a further explanation of the present invention, the followingReference Examples and Examples are given, wherein the word "part(s)" isbased on weight unless otherwise noted and the relationship between"part(s)" and "volume part(s)" corresponds to that between "gram(s)" and"milliliter(s)."

REFERENCE EXAMPLES Reaction of Step(A)

In 80 volume parts of dimethylformamide are dissolved 25 parts oforthohydroxyacetophenone and, while the solution is externally cooled toabout -20° C. with dry ice-acetone, 80 volume parts oftetrachloropyrophosphoric acid are added dropwise to the solution. Theresulting mixture is stirred at room temperature for 13 hours. Then, thereaction mixture is poured into ice water and the resulting crystals arerecovered by filtration, washed with water and ethanol and finallyrecrystallized from acetone. The procedure yields of4-oxo-4H-1-benzopyran-3-carboxaldehyde as colorless crystals melting at152°-153° C.

Analysis for C₁₀ H₆ O₃ Calcd. C, 68.96; H, 3.47; Found C, 68.70; H,3.37.

When N-N-diethyl formaldehyde and N-phenyl N-methylformamide arerespectively employed in place of dimethylformamide in the aboveprocedure, 4-oxo-4H-1-benzopyran-3-carboxaldehyde are produced,respectively.

By the procedure similar to the above reference, the following compoundsare synthesized.

    ______________________________________                                                          Crystal form                                                Starting                Recrystalli-                                                                             Melting                                    materials   Product     zation solvent                                                                           point (° C.)                        ______________________________________                                        2-Hydroxy-5-                                                                              6-Chloro-4- White scales                                          chloroaceto-                                                                              oxo-4H-1-                                                         phenone +   benzopyran-            166-168                                    Dimethyl-   3-carbox-                                                         formamide   aldehyde    Acetone                                               2-Hydroxy-5-                                                                              6-Nitro-4-  Pale yellow                                           nitroaceto- oxo-4H-1-   prisms                                                phenone +   benzopyran-            163-164                                    Dimethyl-   3-carbox-                                                         formamide   aldehyde    Acetone                                               2-Hydroxy-  6,8-Dimethyl-                                                                             Colorless                                             3,5-dimethyl                                                                              4-oxo-4H-1- needles                                               acetophenone                                                                              benzopyran- Dimethyl   186-187                                    + Dimethyl- 3-carbox-   formamide                                             formamide   aldehyde    + Acetone                                             2-Hydroxy-  6,8-Dibromo-                                                                              Colorless                                             3,5-dibromo 4-oxo-4H-1- needles                                               acetophenone                                                                              benzopyran-3-          177-178                                    + Dimethyl- carbox-                                                           formamide   aldehyde    Acetone                                               2-Hydroxy-5-                                                                              6-Dimethyl- Yellow                                                dimethyl    amino-4-oxo-                                                                              needles                                               aminoaceto- 4H-I-benzo- Dimethyl    153-154.5                                 phenone +   pyran-3-    formamide                                             Dimethyl-   carbox-     +                                                     formamide   aldehyde    Acetone                                               2-Hydroxy-5-                                                                              6-Isopropyl-                                                                              Yellow                                                isopropyl   4-oxo-4H-1- needles                                               acetophenone                                                                              benzopyran- Ethylace-   98-99.5                                   + Dimethyl- 3-carbox-   tate +                                                formamide   aldehyde    Petroleum                                                                     ether                                                 2-Hydroxy-5-                                                                              6-Propyl-4- Pale yellow                                           proylaceto- oxo-4H-1-   scales                                                phenone +   benzopyran- Ligroin +  100-102                                    Dimethyl-   3-carboxy-  Ethyl-                                                formamide   aldehyde    acetate                                               2-Hydroxy-5-                                                                              6-n-Butyl-4-                                                                              Colorless                                             n-butyl-    oxo-4H-1-   needles                                               acetophenone                                                                              benzopyran-            86.5-88.5                                  + Dimethyl- 3-carbox-   Ligroin +                                             formamide   aldehyde    Cyclohexane                                           2-Hydroxy-5-                                                                              6-methyl-4- Colorless                                             methylaceto-                                                                              oxo-4H-1-   scales                                                phenone +   benzophran-            174-175                                    Dimethyl-   3-carbox    acetone                                               formamide   aldehyde                                                          2-Hydroxy-4-                                                                              7-Methoxy-4-                                                                              Pale yellow                                           methoxy-    oxo-4H-1-   needles                                               acetophenone                                                                              benzopyran-            188-190                                    + Dimethyl- 3-carbox-                                                         formamide   aldehyde    Acetone                                               2-Hydroxy-5-                                                                              6-Methyoxy-4-                                                                             Pale yellow                                           methoxy-    oxo-4H-1-   plates                                                acetophenone                                                                              benzopyran-3-          165-166                                    + Dimethyl- carbox-                                                           formamide   aldehyde    Acetone                                               2-Hydroxy-6-                                                                              5-Methoxy-4-                                                                              Pale yellow                                           methoxy-    oxo-4H-1-   plates                                                acetophenone                                                                              benzopyran-3-          115-116                                    + Dimethyl- carbox-                                                           formamide   aldehyde    Acetone                                               2-Hydroxy-5-                                                                              6-Ethyl-4-  Colorless                                             ethyl-      oxo-4H-1-   scales                                                acetophenone                                                                              benzopyran-3-          109-111                                    + Dimethyl- carboxaldehyde                                                                            Ethyl-                                                formamide               acetate                                               2-Hydroxo-6-                                                                              5-Acetoxy-4-                                                                              Colorless                                             acetoxy-    oxo-4H-1-   needles                                               acetophenone                                                                              benzopyran-3-          174.5-176.5                                + Dimethyl- carbox-                                                           formamide   aldehyde    Acetone                                               2-Hydroxy-4-                                                                              7-Acetoxy-4-                                                                              Pale yellow                                           acetoxy-    oxo-4H-1-   needles                                               acetophenone                                                                              benzopyran-3-          155-156                                    + Dimethyl- carbox-                                                           formamide   aldehyde    Acetone                                               2-Hydroxy-5-                                                                              6-Carboxy-4-                                                                              Colorless                                             carboxy-    oxo-4H-1-   crystals   271.5-273.5                                acetophenone                                                                              benzopyran-3-          (decomp.)                                  + Dimethyl- carbox-                                                           formamide   aldehyde    Acetone                                               2,4-Dihydroxy-                                                                            7-Hydroxy-4-                                                                              Yellow prisms                                         acetophenone                                                                              oxo-4H-1-              266.5-268.5                                + Dimethyl- benzopyran-3-                                                                             DMF +      (decomp.)                                  formamide   carbox-     Acetone +                                                         aldehyde    H.sub.2 O                                             2-Hydroxy-5-                                                                              6-Acetamino-                                                                              Pale yellow                                           acetamino-  4-oxo-4H-1- powder                                                acetophenone                                                                              benzopyran-3-          231-233                                    + Dimethyl- carbox-                                                           formamide   aldehyde    Acetone                                               ______________________________________                                    

REACTIONS OF STEP (B) AND (C) Reference 1

2.52 Parts of 4-oxo-4H-1-benzopyran-3-carboxaldehyde are admixed wellwith 2.10 parts of hydroxylamine hydrochloride, followed by the additionof 30 volume parts of 95 weight % ethyl alcohol and 0.5 volume part ofconcentrated hydrochloric acid. The whole mixture is refluxed for 6hours and cooled. The resulting precipitate is recovered by filtration,treated with activated carbon and recrystallized from ethanol. Thisprocedure yields 4-oxo-4H-1-benzopyran-3-carbonitrile as colorlesscrystals. Melting point: 177°-178° C.

Analysis for C₁₀ H₅ NO₂ Calcd. C, 70.17; H, 2.95; N, 8.19; Found C,70.00; H, 2.80; N, 8.13.

Reference 2

A mixture of 10.44 parts of 4-oxo-4H-1-benzopyran-3- carboxaldehyde and5.4 parts of cyanoacetic acid are heated in an oil bath at 110° C., andto the mixture 25 volume parts of pyridine are added dropwise over about30 seconds, after which time the whole mixture is further heated for 8minutes. After cooling, the separated crystals are recovered byfiltration, treated with activated carbon and recrystallized three timesfrom ethanol. This procedure yieldstrans-3-(4-oxo-4H-1-benzopyran-3-yl)-acrylonitrile as pale-yellowishprisms. Melting point: 192°-194° C.

Analysis for C₁₂ H₇ NO₂ Calcd. C, 73.09; H, 3.58; N, 7.10; Found C,73.48; H, 3.60; N, 7.01.

By procedures similar to the above procedure, the following compoundsare synthesized.

    ______________________________________                                                        Crystal form                                                  Starting              Recrystalli-                                                                              Melting                                     compound  Product     zation solvent                                                                            point (° C.)                         ______________________________________                                        6-Methyl-4-                                                                             6-Methyl-4- Colorless                                               oxo-4H-1- oxo-4H-1-   needles                                                 benzopyran-                                                                             benzopyran-3-           152.5-153.5                                 3-carbox- carbonitrile                                                        aldehyde              Ethanol                                                 6-Ethyl-4-                                                                              6-Ethyl-4-  Colorless                                               oxo-4H-1- oxo-4H-1-   crystals                                                benzopyran-3-                                                                           benzopyran-3-           123-124                                     carbox-   carbonitrile                                                        aldehyde              Ethanol                                                 6-Chloro-4-                                                                             6-Chloro-4- Yellow                                                  oxo-4H-1- oxo-4H-1-   prisms                                                  benzopyran-3-                                                                           benzopyran-3-           210-213                                     carbox-   carbonitrile                                                        aldehyde              Methanol                                                6-Methoxy-4-                                                                            6-Methoxy-4-                                                                              Colorless                                               oxo-4H-1- oxo-4H-1-   needles                                                 benzopyran-3-                                                                           benzopyran-3-           194-195                                     carbox-   carbonitrile                                                        aldehyde              Ethanol                                                 6-n-Hexyl-4-                                                                            6-n-Hexyl-4-                                                                              Colorless                                               oxo-4H-1- oxo-4H-1-   plates                                                  benzopyran-3-                                                                           benzopyran-3-           55                                          carbox-   carbonitrile                                                                              Ethanol-                                                aldehyde              hexane                                                  7-n-Butoxy-4-                                                                           7-n-Butoxy- Pale yellow                                             oxo-4H-1- 4-oxo-4H-1- plates                                                  benzopyran-3-                                                                           benzopyran-3-           120-121                                     carbox-   carbonitrile                                                                              Benzene-                                                aldehyde              n-Hexane                                                6-Dimethyl-                                                                             6-Dimethyl- Yellow needles                                          amino-4-oxo-                                                                            amino-4-oxo-                                                        4H-1-benzo-                                                                             4H-1-benzo- Chloroform- 167-168                                     pyran-3-  pyran-3-    ethyl                                                   carbox-   carbonitrile                                                                              acetate                                                 aldehyde                                                                      3-Formyl- 3-Cyanobenzo-                                                                             Pale brown                                              benzo(h)- (h)-chromone                                                                              plates      229-230                                     chromone              Acetone     (decomp.)                                   3-Formyl- 3-Cyanobenzo-                                                                             Colorless                                               benzo(f)- (f)-chromone                                                                              needles     194.5-195.5                                 chromone              Ethanol                                                 6-Cyclohexyl-                                                                           6-Cyclohexyl-                                                                             Pale brown                                              4-oxo-4H-1-                                                                             4-oxo-4H-1- plates                                                  benzopyran-3-                                                                           benzopyran-             164-165                                     carbox-   3-carbo-                                                            aldehyde  nitrile     Methanol                                                6-n-Propyl-                                                                             6-n-Propyl- Pale yellow                                             4-oxo-4H-1-                                                                             4-oxo-4H-1- needles                                                 benzopyran-                                                                             benzopyran-             102-104                                     3-carbox- 3-carbonit-                                                         aldehyde  rile        Ethanol                                                 6-Isopropyl-                                                                            6-Isopropyl-                                                                              Pale yellow                                             4-oxo-4H-1-                                                                             4-oxo-4H-1- needles                                                 benzopyran-3-                                                                           benzopyran-3-                                                                             118-120                                                 carbox-   carbonitrile                                                        aldehyde              Ethanol                                                 7-Methoxy-4-                                                                            7-Methyoxy-4-                                                                             Pale yellow                                             oxo-4H-1- oxo-4H-1-   needles                                                 benzopyran-3-                                                                           benzopyran-3-           191-193                                     carbox-   carbonitrile                                                        aldehyde              Methanol                                                6-n-Butyl-4-                                                                            6-n-Butyl-4-                                                                              Colorless                                               oxo-4H-1- oxo-4H-1-   needles                                                 benzopyran-3-                                                                           benzopyran-             94-95                                       carbox-   3-carbo-                                                            aldehyde  nitrile     Ethanol                                                 6-n-Butyl-4-                                                                            Trans-3-(6- Colorless                                               oxo-4H-1- n-Butyl-4-  needles                                                 benzopyran-3-                                                                           oxo-4H-1-               124-126                                     carbox-   benzopyran-3-                                                       aldehyde  yl)-acrylo- Ligroin-                                                          nitrile     Benzene                                                 6-Nitro-4-                                                                              6-Nitro-4-  Colorless                                               oxo-4H-1- oxo-4H-1-   plates                                                  benzopyran-3-                                                                           benzopyran-3-           211-213                                     carbox-   carbonitrile                                                                              Methanol-                                               aldehyde              Chloroform                                              7-Acetoxy-4-                                                                            7-Hydroxy-4-                                                                              Colorless                                               oxo-4H-1- oxo-4H-1    needles                                                 benzopyran-3-                                                                           benzopyran-3-           278-280                                     carbox-   carbonitrile                                                        aldehyde              Ethanol                                                 6-Ethoxy- 6-Ethoxy-   Colorless                                               carbonyl  carbonyl    needles                                                 4-oxo-                                                                        4-oxo-                                                                        4H-1-benzo-                                                                             4H-1-benzo-             164-165                                     pyran-3-  pyran-3-                                                            carbox-   carbonitrile                                                        aldehyde              Benzene                                                 6,8-Dimethyl-                                                                           6,8-Dimethyl-                                                                             Colorless                                               4-oxo-4H-1-                                                                             4-oxo-4H-1- needles                                                 benzopyran-3-                                                                           benzopyran-3-           196-198                                     carbox-   carbonitrile                                                        aldehyde              Acetone                                                 7-Acetoxy-4-                                                                            7-Acetoxy-4-                                                                              Colorless                                               oxo-4H-1- oxo-4H-1-   hairly                                                  benzopyran-                                                                             benzopyran- crystals    182-183                                     3-carbox- 3-carbonitrile          (decomp.)                                   aldehyde              Ethanol                                                 7-Benzoyloxy                                                                            7-Benzoyloxy                                                                              Plates                                                  4-oxo-4H-                                                                     4-oxo-4H-                                                                     1-benzo-  1-benzo-                200-202                                     pyran-3-  pyran-3-    Ethanol-                                                carbox-   carbonitrile                                                                              tetrahydro-                                             aldehyde              furan                                                   6,7-Dihydroxy                                                                           6,7-Dihydroxy                                                                             Pale brown                                              4-oxo-4H-1-                                                                   4-oxo-4H-1-                                                                             powder      higher                                                  benzopyran-                                                                             benzopyran-3-                                                                             Dimethyl-   than                                        3-carbox- carbonitrile                                                                              formamide-  300                                         aldehyde              water                                                   ______________________________________                                    

EXAMPLES Example 1

To 100 volume parts of dry tetrahydrofuran are added 4.28 parts ofcomminuted anhydrous aluminum chloride, 2.50 parts of4-oxo-4H-1-benzopyran-3-carbonitrile and 4.18 parts of sodium azide inthis order and, the whole mixture is refluxed under stirring for 23hours. Then, to the resulting mixture 35 volume parts of 15 weight%hydrochloric acid are added, followed by distilling off tetrahydrofuranunder reduced pressure. The resulting solid residue is recovered byfiltration and recrystallized from dimethylformamide. This procedureyields 3-(1H-tetrazol-5-yl) chromone as colorless hairy needles. Meltingpoint: 284°-285° C.(decomp. with foaming).

Analysis for C₁₀ H₆ N₄ O₂ Calcd. C, 56.07; H, 2.82; N, 26.16; Found C,56.16; H, 2.60; N, 26.27.

EXAMPLE 2

Under stirring, 4.6 parts of anhydrous aluminum chloride are added to100 volume parts of dry tetrahydrofuran, followed by the addition of3.11 parts of trans-3-(4-oxo-4H-1-benzopyran-3-yl)-acrylonitrile and 4.5parts of sodium azide. The whole mixture is refluxed for 28 hours and,then, 35 volume parts of 15 weight% hydrochloric acid are added to theresulting mixture, followed by distilling off tetrahydrofuran underreduced pressure. The resulting residue is recovered by filtration andrecrystallized from methanol, dimethylformamide-water and, then, frommethanol. This procedure yieldstrans-1-(4-oxo-4H-1-benzopyran-3-yl)-2-(1H-tetrazol-5-yl) ethylene aslight-yellow needles. Melting point: 254.5°-255° C.(decomp. withfoaming).

Analysis for C₁₂ H₈ N₄ O₂ Calcd. C, 60.00; H, 3.36; N, 23.32; Found C,59.98; H, 3.25; N, 23.15.

Mass spectrum: m/e 240(M⁺), 212, 196.

By procedures similar to the procedure described above, the followingcompounds are synthesized.

    ______________________________________                                                        Crystal form                                                  Starting              Recrystalli-                                                                              Melting                                     compound  Product     zation solvent                                                                            point (° C.)                         ______________________________________                                        6-Methyl-4-                                                                             3-(1H-Tetra-                                                                              Colorless                                               oxo-4H-1- zol-5-yl)-  scales      258-259                                     benzopyran-                                                                             6-methyl-               (decomp.)                                   3-carbo-  chromone    Dimethyl-                                               nitrile               formamide                                               6-Ethyl-4-                                                                              3-(1H-Tetra-                                                                              Colorless                                               oxo-4H-1- zol-5-yl)-  needles                                                 benzopyran-                                                                             6-ethyl-    Dimethyl-   217-218                                     3-carbo-  chromone    formamide-                                              nitrile               water                                                   6-Chloro-4-                                                                             3-(1H-Tetra-                                                                              Colorless                                               oxo-4H-1- zol-5-yl)-  needles     267.5                                       benzopyran-                                                                             6-chloro-   Dimethyl-   (decomp.)                                   3-carbonit-                                                                             chromone    formamide-                                              rile                  water                                                   6-Methoxy-                                                                              3-(1H-Tetra-                                                                              Colorless                                               4-oxo-4H- zol-5-yl)-6-                                                                              hairy       281-282                                     1-benzo-  methoxy-    needles     (decomp.                                    pyran-3-  chromone    Dimethyl-   with                                        carbo-                formamide-  foaming)                                    nitrile               water                                                   6-n-Hexyl-4-                                                                            3-(1H-Tetra-                                                                              Colorless                                               oxo-4H-1- zol-5-yl)-6-                                                                              plates                                                  benzopyran-                                                                             n-hexyl-    Dimethyl-   207-210                                     3-carbo-  chromone    formamide-                                              nitrile               methanol                                                7-n-Butoxy-4-                                                                           3-(1H-Tetra-                                                                              Colorless   236-238                                     oxo-4H-1- zol-5-yl)-7-                                                                              colum       (decomp.                                    benzopyran-                                                                             n-butoxy-   Dimethyl-   with                                        3-carbo-  chromone    formamide-  foaming)                                    nitrile               acetone                                                 6-Dimethyl-                                                                             3-(1H-Tetra-                                                                              Orange crystall                                                                           303-305                                     amino-4-oxo-                                                                            zol-5-yl)-6-                                                                              powder      (decomp.                                    4H-1-benzo-                                                                             dimethyl-   Dimethyl-   with                                        pyran-3-  aminochromone                                                                             formamide-  foaming)                                    carbonitrile          acetone                                                 3-Cyanobenzo-                                                                           3-(1H-Tetra-                                                                              Pale brown  303-305                                     (h)chromone                                                                             zol-5-yl)-  rhombous    (decomp.                                              benzo(h)-   Dimethyl-   with                                                  chromone    formamide-  foaming)                                                          water                                                   3-Cyanobenzo-                                                                           3-(1H-Tetra-                                                                              Colorless   282-285                                     (f)chromone                                                                             zol-5-yl)-  prisms      (decomp.                                              benzo(f)-   Dimethyl-   with                                                  chromone    formamide-  foaming)                                                          water                                                   6-Cyclohexyl-                                                                           3-(1H-Tetra-                                                                              Colorless                                               4-oxo-4H-1-                                                                             zol-5-yl)-6-                                                                              needles                                                 benzopyran-3-                                                                           cyclohexyl- Methanol-   252-253                                     carbonitrile                                                                            chromone    tetrahydro-                                                                   furan                                                   6-n-Propyl-4-                                                                           3-(1H-Tetra-                                                                              Colorless                                               oxo-4H-1- zol-5-yl)-6-                                                                              needles                                                 benzopyran-3-                                                                           n-propyl-   Dimethyl-   214-215                                     carbonitrile                                                                            chromone    formamide-                                                                    methanol                                                6-iso-Propyl-                                                                           3-(1H-Tetra-                                                                              Colorless                                               4-oxo-4H-1-                                                                             zol-5-yl)-6-                                                                              needles                                                 benzopyran-3-                                                                           iso-propyl- Dimethyl-   222-223                                     carbonitrile                                                                            chromone    formamide-                                                                    methanol                                                7-Methoxy-4-                                                                            3-(1H-Tetra-                                                                              Colorless                                               oxo-4H-1- zol-5-yl)-7-                                                                              prisms      277-279                                     benzopyran-3-                                                                           methoxy-    Dimethyl-                                               carbonitrile                                                                            chromone    formamide                                               6-n-Butyl-4-                                                                            3-(1H-Tetra-                                                                              Colorless                                               oxo-4H-1- zol-5-yl)-6-                                                                              needles                                                 benzopyran-3-                                                                           n-butyl-    Dimethyl-   206-209                                     carbonitrile                                                                            chromone    formamide-                                                                    methanol                                                Trans-3-(6-n-                                                                           Trans-1-(6-n-                                                                             Pale yellow fine                                        Butyl-4-oxo-                                                                            butyl-4-oxo-                                                                              needles                                                 4H-1-benzo-                                                                             1-benzopyran-           247.5-250                                   pyran-3)- 3-yl)-2-(1H-                                                                              Dimethyl-                                               acrylontrile                                                                            tetrazol-5- formamide-                                                        yl)ethylene acetone                                                 6-Nitro-4-                                                                              3-(1H-Tetra-                                                                              Colorless   285-286                                     oxo-4H-1- zol-5-yl)-6-                                                                              needles     (decomp.                                    benzopyran-3-                                                                           nitrochromone                                                                             Dimethyl-   with                                        carbonitrile          formamide   foaming)                                    7-Hydroxy-4-                                                                            3-(1H-Tetra-                                                                              Colorless                                               oxo-4H-1- zol-5-yl)-7-                                                                              needles                                                 benzopyran-3-                                                                           hydroxy-    Dimethyl-   higher                                      carbonitrile                                                                            chromone    formamide-  than 300                                                          water                                                   6-Amino-4-                                                                              3-(1H-Tetra-                                                                              Reddish-yellow                                          oxo-4H-1- zol-5-yl)-6-                                                                              plate                                                   benzopyran-3-                                                                           aminochromone                                                                             Dimethyl-   higher                                      carbonitrile          formamide   than 300                                                          water                                                   6-Ethoxy- 3-(1H-Tetra-                                                                              Colorless                                               carbonyl- zol-5-yl)-  needles     271-273                                     4-oxo-4H- 6-ethoxy-               (decomp.                                    1-benzo-  carbonyl-   Dimethyl-   with                                        pyran-3-  chromone    formamide-  foaming)                                    carbonitrile          acetone                                                 6,8-Dimethyl-                                                                           3-(1H-Tetra-                                                                              Colorless   274-275                                     4-oxo-4H-1-                                                                             zol-5-yl)-  needles     (decomp.                                    benzopyran-                                                                             6,8-dimethyl-           with                                        3-carbo-  chromone    Dimethyl-   foaming)                                    nitrile               formamide                                               7-Acetoxy-                                                                              3-(1H-Tetra-                                                                              Colorless   247-248                                     4-oxo-4H- zol-5-yl)-  micro       (decomp.                                    1-benzopyran-                                                                           7-acetoxy-  crystals    with                                        3-carbo-  chromone    Dimethyl-   foaming)                                    nitrile               formamide                                               7-Benzoyl-                                                                              3-(1H-Tetra-                                                                              Colorless                                               oxy-4-oxo-                                                                              zol-5-yl)-  plates                                                  4H-1-benzo-                                                                             7-benzoyloxy-                                                                             Dimethyl-   243-245                                     pyran-3-  chromone    formamide-                                              carbonitrile          ethanol                                                 6,7-Dihydroxy-                                                                          3-(1H-Tetra-                                                                              Colorless   higher                                      4-oxo-4H-1-                                                                             zol-5-yl)-6,                                                                              needles     than                                        benzopyran-3-                                                                           7-dihydroxy-                                                                              Dimethyl-   300                                         carbonitrile                                                                            chromone    formamide-                                                                    water                                                   ______________________________________                                    

EXAMPLE 3

To 140 parts of aquous solution containing 8 parts of sodium carbonate,20 parts of 3-(1H-tetrazol-5-yl)-6-ethylchromone are added, and followedby heating. After cooling, insoluble portion is removed by filtrationand the resulting mother liquid is cooled. This procedure gives sodium3-(1H-tetrazol-5-yl)-6-ethylchromon as pale yellow crystal melting at286°-288° C. (decomp.)

Analysis for C₁₂ H₉ N₄ O₂ Na.2H₂ O Calcd. C, 48.00; H, 4.36; N, 18.66;Found C, 48.02; H, 4.46; N, 18.76.

EXAMPLE 4

0.112 Part of 3-(1H-tetrazol-5-yl)-6-ethylchromone and 0.0895 part ofDL-methylephedrine are added to 5 parts of ethanol under stirring. Theresulting solution is concentrated to dryness, and the precipitatedresidue is recrystallized from 2 parts of ethanol. This procedure gives3-(1H-tetrazol-5-yl)-6-ethylchromone DL-methylephedrine salt ascolorless plates melting at 172° C.

Analysis for C₂₃ H₂₇ O₃ N₅ Calcd. C, 65.53; H, 6.45; N, 16.61; Found C,65.79; H, 6.52; N, 16.44.

By a procedure similar to that described above, the following compoundsare obtained.

    ______________________________________                                                         Crystal form                                                 Starting               Recrystalli-                                                                              Melting                                    compound   Product     zation solvent                                                                            point (° C.)                        ______________________________________                                        3-(1H-Tetra-                                                                             Diethanol-  Colorless                                              zol-5-yl)-6-                                                                             amine salt  plates                                                 ethylchromone                      150                                        +                      Ethanol                                                Diethanol-                                                                    amine                                                                         3-(1H-Tetra-                                                                             Monoethanol-                                                                              Colorless                                              zol-5-yl)-6-                                                                             amine salt  needles                                                ethylchromone                      152                                        +                      Ethanol                                                Monoetha-                                                                     nolamine                                                                      3-(1H-Tetra-                                                                             Diethylamine                                                                              Colorless                                              zol-5-yl)-6-                                                                             salt        scales                                                 ethylchromone                      223                                        +                      Ethanol-                                               Diethyl-               ethylether                                             amine                                                                         ______________________________________                                    

EXAMPLE 5

0.244 Part of 3-(1H-tetrazol-5-yl)-6-methoxychromone is added to 8 partsof 57 weight % hydrojodic acid, and the whole mixture is heated at 140°C. for 2 hours.

Resulting insoluble portion is collected by filtration andrecrystallized from dimethyl formamide-water, whereby3-(1H-tetrazol-5-yl)-6-hydroxychromone is obtained as colorless needlesmelting at higher than 300° C.

Analysis for C₁₀ H₆ N₄ O₃ Calcd. C, 52.18; H, 2.63; N, 24.34; Found C,51.81; H, 2.68; N, 24.16.

I.R. spectrum (KBr)cm⁻¹ : 1635, 1610, 1588 (chromone), 1540.

N.M.R. spectrum (d₆ -DMSO) δ: 10.5(1H, broad, OH), 9.25 (1H, singlet, C₂-H), 7.2-7.8(3H, multiplet).

EXAMPLE 6

Some examples of practical recipes in which the compounds of thisinvention are utilized as remedies for an allergic disease are asfollows:

    ______________________________________                                         A.(Tablet)                                                                   ______________________________________                                        (1)   3-(1H-tetrazol-5-yl)-6-ethylchromone                                                                 20 mg.                                           (2)   lactose                35 mg.                                           (3)   corn starch            150 mg.                                          (4)   microcrystalline cellulose                                                                           30 mg.                                           (5)   magnesium stearate     5 mg.                                                                         240 mg.                                                                       per tablet                                       ______________________________________                                    

(1), (2), (3), 2/3 quantity of (4) and half quantity of (5) arethroughly mixed, and then the mixture is granulated. Remaining 1/3quantity of (4) and half of (5) are added to the granules and compressedinto tablets. Thus prepared tablets can further be coated with asuitable coating agent, e.g. sugar.

    ______________________________________                                        B.(Capsule)                                                                   ______________________________________                                        (1)   3-(1H-tetrazol-5-yl)-6-ethylchromone                                                                 20 mg.                                           (2)   lactose                102 mg.                                          (3)   microcrystalline cellulose                                                                           70 mg.                                           (4)   magnesium stearate     8 mg.                                                                         200 mg.                                                                       per capsule                                      ______________________________________                                    

(1), (2), (3) and half quantity of (4) are throughly mixed, and then themixture is granulated. Remaining half of (4) is added to the granulesand the whole is filled into a gelatin capsule.

    ______________________________________                                        C.(Injection)                                                                 ______________________________________                                        (1)   sodium 3-(1H-tetrazol-5-yl)-6-                                                ethylchromone        10 mg.                                             (2)   inositol             100 mg.                                            (3)   benzyl alcohol       20 mg.                                             ______________________________________                                    

All ingredients are dissolved in water to make 2.0 ml. of the solution(pH 7.5) serving as injection.

We claim:
 1. A compound of the formula ##STR6## wherein m is 2 and eachR when taken alone represents straight or branched alkyl up to 6 carbonatoms or when taken together represent butadienylene (--CH═CH--CH═CH--)which forms a benzene ring with any two adjacent carbon atoms atpositions 5, 6, 7 and
 8. 2. A compound as claimed in claim 1, wherein Rrepresents straight chain alkyl up to 6 carbon atoms.
 3. A compound asclaimed in claim 1, wherein the R's when taken together representbutadienylene which forms a benzene ring with any two adjacent carbonatoms at positions 5, 6, 7 and
 8. 4. A compound of the formula ##STR7##wherein m is 1 and R represents 6-halogen.
 5. The compound6-methoxy-4-oxo-4H-1-benzopyran-3-carbonitrile.
 6. The compound7-methoxy-4-oxo-4H-1-benzopyran-3-carbonitrile.
 7. The compoundaccording to claim 2 which is6,8-dimethyl-4-oxo-4H-1-benzopyran-3-carbonitrile.
 8. The compoundaccording to claim 3 which is 3-cyanobenzo[h]chromone.
 9. The compoundaccording to claim 3 which is 3-cyanobenzo[f]chromone.
 10. The compoundaccording to claim 4 which is6-chloro-4-oxo-4H-1-benzopyran-3-carbonitrile.